Continuous-flow technology involves the continuous introduction of a stream of chemical reactants into a flow or microreactor to yield a desired reaction product on a continuous basis (1, 2). Continuous-flow technology offers potential advantages compared with traditional batch manufacturing of pharmaceuticals, such as greater optimization and control of the process, improved safety and environmental profiles for a given process, and a reduced manufacturing
footprint (1,2). Pharmaceutical companies, fine-chemical producers, and academia are pursuing continuous-flow chemistry in the production of APIs and related relevant reactions with several interesting developments in this field.

Evaluating the technology

In general, microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer (1, 3). Microstructured devices operate in a continuous-flow environment, which can provide controlled process conditions, high flow rates, and high mass throughput. Continuous operations also may allow for bulk-chemistry processes to have high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment, such as pressure loss, heat-transfer characteristics, residence time, and mixing time (1-4). The high surface-area-to-volume ratio comparative to a batch reactor enables better temperature control overall, including for exothermic reactions, which improves processing conditions. Scale-up issues may be minimized due to maintaining improved mixing and heat transfer.

Recent activity

These benefits are attracting investment and R&D in continuous-flow chemistry. In February 2013, DSM Pharmaceutical Products signed an agreement with Chemtrix, a supplier of flow-chemistry equipment and services, for providing equipment, development, and manufacturing services to the pharmaceutical industry. Chemtrix specializes in ready-to-use laboratory and kilo-scale microreactors as well as reactor and process design for industrial reactors. DSM provides drug-synthesis route development, scale-up, and implementation of continuous-flow processes for manufacturing. DSM has FDA approval for using microreactors for making a pharmaceutical product at commercial scale under cGMP at its facility in Linz, Austria, where its dedicated commercial-scale installation is located. Initially, the DSM–Chemtrix collaboration will offer an industrial flow process-development package for customized scalable flow-chemistry solutions. The package covers all phases of process design, scanning chemistries, chemistry development, route scouting, equipment design, and scale-up for fully continuous or integrated processes.

Reflecting growing interest in microreactor technology for fine-chemical manufacturing, Lonza invested in what it terms the “Factory of Tomorrow,” at its facility in Visp, Switzerland. The investment, made in 2012, enables production of multitons of intermediates and/or APIs based on continuous-flow processing. Lonza operates assets that can produce several kilograms to several tons of small-molecule APIs using microreactors, and the new unit in Visp adds an integrated solution where all common unit operations in flow can be streamlined in a flexible fashion using microreactors (FlowPlate, Lonza) (1). This new unit integrates a range of flow reactors, such as continuous stirrer-tank reactors or ultrasounds and streamlines flow processes, including work-up unit operations, such as liquid–liquid extraction and distillation (wiped-film, thin film). Higher pressure applications are enabled as well by allowing gas–liquid reactions, such as ozone and HCN chemistries. The technology can be used for chemical reactions under severe and extreme conditions, such as high temperatures or cryogenic conditions (1).